Recurrent breast cancer is typically an incurable disease. Consequently, the tendency of breast cancers to recur following treatment is the most important determinant of clinical outcome. Recurrent tumors invariably arise from the reservoir of residual tumor cells (RTCs) that can persist in patients in a presumed dormant state for many years after treatment of their primary tumor. As such, minimal residual disease, tumor dormancy, and recurrence constitute fundamental manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Despite the unrivaled clinical importance of these aspects of breast cancer progression, however, the mechanisms underlying them are largely unknown. Consequently, understanding the biology of RTCs and elucidating the molecular pathways that contribute to tumor dormancy and recurrence is a critical priority in cancer research. We propose that disabling the survival mechanisms by which dormant RTCs persist in breast cancer patients following treatment will deplete this critical reservoir of cells, reduce tumor recurrence, and thereby improve survival. Using genetically engineered mouse models that faithfully recapitulate tumor dormancy and recurrence, we have determined that uPAR and its binding partner, ?5 integrin, are markedly down-regulated in dormant RTCs, but are subsequently up-regulated, along with FAK activity, in spontaneous recurrent tumors that arise with a stochastic latency period. When taken together with the observations that elevated uPAR and ?5 integrin expression are each strongly associated with an increased risk of recurrence in women with breast cancer, we hypothesize that down-regulation of uPAR and ?5?1 integrin are required for entrance into the dormant state following therapy, and that subsequent up-regulation of uPAR/?5?1/FAK signaling promotes mammary tumor recurrence by inducing the re-entry of dormant RTCs into the cell cycle. The specific aims of this proposal are to: (1) Define uPAR/?5?1/FAK pathway status in residual disease in mice and in patients. uPAR/?5?1/FAK pathway activation will be evaluated in primary tumors, recurrent tumors, RTC in the mammary gland, and DTC in the BM and lungs in GEM models following targeted therapy or chemotherapy. Companion studies will evaluate the uPAR/?5?1/FAK pathway in BM DTCs, as well as primary and recurrent metastatic tumor cells in breast cancer patients; and (2) Determine the impact of uPAR/?5?1/ FAK pathway modulation on residual disease and recurrence. By probing the biology of RTCs and the pathways that contribute to tumor recurrence, the proposed studies will advance the therapeutic goals of maintaining tumor cells in a dormant state, inducing their death by targeting their survival mechanisms, or blocking preferred pathways of recurrence. We anticipate that this knowledge will facilitate the development of more effective therapeutic approaches to recurrence that could improve the treatment options available to millions of breast cancer survivors.